Role of PI3K signaling pathway in endotoxin-induced leptin resistance

• Grant number: 13/03915-0
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: July 31, 2013
• End date: July 30, 2014
• Field of knowledge: Biological Sciences - Physiology - General Physiology
• Principal Investigator: Lucila Leico Kagohara Elias
• Grantee: Beatriz de Carvalho Borges Del Grande
• Supervisor: Carol Fuzeti Elias
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Institution abroad: University of Michigan, United States

Abstract

During the endotoxemia acutely induced by the lipopolysaccharide (LPS) (100micrograms/kg), we observed hypophagia and reduced body weight gain, in addition to the increased production of inflammatory cytokines. These responses are associated with increased plasma leptin levels. However, animals treated with repeated doses of LPS did not show hypophagia and reduced body weight gain, indicating the development of endotoxin tolerance. We observed that this phenomenon is associated with no alterations in plasma leptin levels, and an impaired leptin signaling in the hypothalamus, suggesting the development of leptin resistance induced by repeated stimulation with endotoxin. The interaction of leptin with LepRb receptor in the hypothalamus results in the activation of three different signaling pathways, the JAK / STAT, the SHP-2 and MAPK / ERK and PI3K pathway. We observed that animals with single LPS injection and treated with PI3K inhibitor exhibit reversion of hypophagia induced by LPS, evidencing the participation of PI3K in the anorexia during acute endotoxemia. The PI3K pathways in the hypothalamus are activated after interaction of leptin with its receptor. Data from the literature show the involvement of PI3K in the anorexia induced by leptin, as the central administration of PI3K inhibitors followed by injection of leptin, reverse anorexia. It was recently shown that deletion of PI3K in proopiomelanocortin expressin neurons in the arcuate nucleus blocks the effects of leptin on these neurons. The PI3K pathway regulates the responses induced by LPS in monocytes and macrophages. However, there is no study investigating the involvement of PI3K in the food intake reduction induced by acute LPS treatment. Thus, in the present study we aim to examine the functional contribution of the PI3K pathway in hypophagia induced by single dose of LPS. To achieve this objective, we will perform our experiments in knockout mice for p110± catalytic subunit of PI3K specifically in neurons that express the leptin receptor. Furthermore, we also intend to generate by the Cre-loxP technology, knockout mice for PTEN protein, a couteregulator of PI3K pathway, specifically in neurons that express the leptin receptor. In these mice we will evaluate the participation of PTEN in the leptin resistance after long term exposure to endotoxin. (AU)

Scientific publications

(4)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BORGES, BEATRIZ C.; GARCIA-GALIANO, DAVID; CRUZ-MACHADO, SANSERAY DA SILVEIRA; HAN, XINGFA; GAVRILINA, GALINA B.; SAUNDERS, THOMAS L.; AUCHUS, RICHARD J.; HAMMOUD, SAHER S.; SMITH, GARY D.; ELIAS, CAROL F.. Obesity-Induced Infertility in Male Mice Is Associated With Disruption of Crisp4 Expression and Sperm Fertilization Capacity. Endocrinology, v. 158, n. 9, p. 2930-2943, SEP 2017. (13/03915-0, 12/16536-4)

BORGES, BEATRIZ C.; ELIAS, CAROL F.; ELIAS, LUCILA L. K.. PI3K signaling: A molecular pathway associated with acute hypophagic response during inflammatory challenges. Molecular and Cellular Endocrinology, v. 438, n. C, p. 36-41, DEC 15 2016. (13/03915-0, 13/09799-1)

RIVAS, PRISCILA M. S.; VECHIATO, FERNANDA M. V.; BORGES, BEATRIZ C.; RORATO, RODRIGO; ANTUNES-RODRIGUES, JOSE; ELIAS, LUCILA L. K.. Increase in hypothalamic AMPK phosphorylation induced by prolonged exposure to LPS involves ghrelin and CB1R signaling. Hormones and Behavior, v. 93, p. 166-174, JUL 2017. (13/03915-0, 13/09799-1, 12/18179-4)

GARCIA-GALIANO, DAVID; BORGES, BEATRIZ C.; DONATO, JR., JOSE; ALLEN, SUSAN J.; BELLEFONTAINE, NICOLE; WANG, MENGJIE; ZHAO, JEAN J.; KOZLOFF, KENNETH M.; HILL, JENNIFER W.; ELIAS, CAROL F.. PI3K alpha inactivation in leptin receptor cells increases leptin sensitivity but disrupts growth and reproduction. JCI INSIGHT, v. 2, n. 23, DEC 7 2017. (13/03915-0)